Tissue engineering including the use of biomaterials offers a novel route for repairing damaged or diseased tissues by incorporating the patients' own healthy cells or donated cells into temporary housings or scaffolds as well as sealing and/or joining severed tissues. The structure and properties of the scaffold are critical to ensure normal cell behaviour and performance of the cultivated or repaired tissue. Biomaterials play a crucial role in such schemes by offering flexible design opportunities, directing subsequent cellular behaviour or function, as well as facilitating resorption rates and ultimate tissue form and strength.
A range of approaches has been used for the construction and assembly of such biomaterials, including the use of a number of synthetic materials, but it is clear that materials from natural sources are superior because of their inherent properties of biological recognition, and their susceptibility to cell-triggered proteolytic breakdown and remodelling.
Natural protein such as extracellular matrix (ECM) proteins show promise in tissue engineering applications because of their biocompatibility, but have been found to be lacking in many areas as a result of inappropriate physical properties. For example, McManus et al (2006) have found that electrospun fibrinogen has insufficient structural integrity for implantation, and instead employed an electrospun fibrinogen-polydioxanone (PDS) composite scaffold for urinary tract reconstruction. Fibrinogen, collagen, elastin, haemoglobin and myogloglobin are reported to have been electrospun (Barnes et al, 2006). The electrospinning process involves imparting a charge to a polymer solution (or melt) and drawing the charged solution into a nozzle. As the electrostatic charges within the solution overcome the surface tension, a liquid jet is initiated at the nozzle. The liquid jet is directed to a rotating mandrel some distance away. As the solution travels the solvent evaporates, and a film is deposited on the mandrel, thus a non-woven, fibrous mat is produced. Additionally, fibrin microbeads and nanoparticles are described in WO 03/037248 (Hapto Biotech, Inc.) and comprise beads of fibrinogen and thrombin manufactured by mixing an aqueous solution of fibrinogen, thrombin and Factor XIII and oil at 50-80 C to form an emulsion. To form nanoparticles the emulsion so-formed is homogenised and the nanoparticles isolated by filtration as a fibrin clot created following cleavage of fibrinogen under the influence of thrombin and Factor VIII. However, these beads and fibres are limited in their shape configuration and flexibility.
Biomaterials such as tissue adhesives have been suggested as alternatives in surgical procedures to physical procedures of connecting tissues such as sutures and staples. Tissue adhesives will hold cut or separated areas of tissue together to allow healing and/or serve as a barrier to leakage, depending on the application. The adhesive should break down or be resorbed and it should not hinder the progress of the natural healing process.
Ideally, the agent should promote the natural mechanism of wound healing and then degrade.
Tissue adhesives are generally utilized in three categories:
i) Hemostasis (for example, by improving in vivo coagulation systems, tissue adhesion itself has a hemostatic aim and it is related to patient clotting mechanisms)
ii) Tissue sealing: primary aim is to prevent leaks of various substances, such as air or lymphatic fluids.
iii) Local delivery of exogenous substances such as medications, growth factors, and cell lines.
One accepted value of fibrin glues lies in their unique physiologic action, which mimics the early stages of the blood coagulation process and wound healing; the part of the normal coagulation cascade to produce an insoluble fibrin matrix. Fibrinogen is a plasma protein which is naturally cleaved to soluble fibrin monomers by the action of activated thrombin. These monomers are cross-linked into an insoluble fibrin matrix with the aid of activated factor XIII. The adhesive qualities of consolidated fibrin sealant to the tissue may be explained in terms of covalent bonds between fibrin and collagen, or fibrin, fibronectin and collagen. Fibrin glues act as both a hemostatic agent and as a sealant. They are bioabsorbable (due to in vivo thrombolysis). Degeneration and reabsorption of the resulting fibrin clot is achieved during normal wound healing.
All fibrin sealants in use as of 2008 have multi-component having two major ingredients, fibrinogen and thrombin and optionally human blood factor XIII and a substance called aprotinin, which is derived from cows' lungs. Factor XIII is a compound that strengthens blood clots by forming covalent cross-links between strands of fibrin. Aprotinin is a protein that inhibits the enzymes that break down blood clots. However these sealants being multicomponent require double barrelled syringes, reconstitution of the multiple components and require exquisite mixing during application to give rise to a uniform and efficious glue.
In an effort to develop a single component protein derived biomaterial, purified thrombin has been developed and now marketed to controlling bleeding during surgery. Upon its application to the tissue site the thrombin cleaves endogenous fibrinogen to produce fibrin in vivo. It is well known that fibrin (which forms the fibrillar matrix on thrombin cleavage of fibrinogen) self-associates (Mosesson MW (2005) Mosesson et al MW, 2001). Factor XIII may be co-administered, and causes dimerisation of the 7-chain of fibrinogen in association with its cleavage by thrombin (Furst W, et al (2007). The success of the procedure relies upon Factor XIII-mediated crosslinking (Lee M G and Jones D (2005) to stabilise the thrombin-derived clot, and a process of stabilising the clot which does not rely on the presence of Factor XIII would be desirable. This single component biomaterial is limited in its applicability, can practically only be used for small bleeds, and the resultant clot, which is slow to form typically has low mechanical strength.
Despite the availability of all of these different biomaterials for the surgeon to use in various surgical procedures there still remains a need for a simple biomaterial that is tunable in its mechanical and biological properties, is easy to use and apply and can be used in a variety of applications for a variety of diseases and surgical procedures.